Concentration-Responsive Gd-DOTA Nanomicelles via Chain-Length Engineering for Transporter-Independent Hepatobiliary...

Balancing the thermodynamic stability and biological clearance of supramolecular assemblies represents a fundamental challenge in the design of functional nanomedicines. To address this, we propose a concentration-responsive "assemble-for-uptake, disassemble-for-clearance" strategy implemented via rational molecular engineering of a minimalist, single-component Gd-DOTA amphiphile. We demonstrate that the alkyl chain length acts as a precise molecular dial to tune the critical micelle concentration (CMC), thereby dictating micellar stability, biological identity, and clearance pathways. Through this tuning, we identified Gd-C12 as the optimized agent, which self-assembles into spherical nanomicelles (38.6 ± 8.3 nm) with desirable T₁ contrast (r₂/r₁ < 2) and kinetic stability surpassing unmodified Gd-DOTA. In vivo studies reveal that Gd-C12 provides potent hepatic enhancement (120% increase) via favorable MPS recognition, independent of organic anion-transporting polypeptide (OATP). Crucially, following hepatic uptake, the agent undergoes spontaneous disassembly upon physiological dilution/excretion, facilitating rapid systemic clearance (>97%) to resolve long-term retention concerns. This work presents Gd-C12 as a high-performance, transporter-independent contrast agent that bridges the gap between nanoparticles and small molecules, holding promise for providing reliable hepatic parenchymal enhancement regardless of OATP expression levels.